The prefrontal cortex (PFC) is involved in the ability to use previously acquired information to guide forthcoming action, termed working memory. The cellular processes underlying working memory are regulated by both inhibitory neurons and dopamine (DA). Dysfunction of inhibitory and DA systems in the PFC is also thought to underlie aspects of schizophrenia, yet the manner in which these systems interact, is relatively unknown. The main goal of the proposed research is to study the mechanisms of dopamine (DA) modulation of inhibition in the prefrontal cortex (PFC). Preliminary data showed that dopamine has temporally biphasic effects on inhibitory postsynaptic potentials (IPSCs) onto pyramidal neurons in the PFC, producing an initial D2-mediated reduction in IPSC amplitude, followed some minutes later by a D1- mediated increase in IPSC amplitude. Based on preliminary data it was hypothesized that the D1 mediated increase in IPSCs was due to increased excitability of interneurons and their axons. Proposed experiments will test this hypothesis by investigating the direct effect of D1 agonists on ionic currents in subtypes of interneurons as well as potential D1 receptor effects on synaptic inputs to interneurons in PFC brain slices. In addition, we will test whether the signaling cascades mediating the D1 effects involve adenylate cyclase and protein kinase A, as in other brain regions, by using selective agents which either inhibit or activate these molecules. Preliminary data also showed an interesting interaction between acetylcholine (Ach) and D2 receptors. Specifically, Ach muscarinic antagonists eliminated the D2-mediated reduction in IPSCs while muscarinic agonists mimicked the D2 effect. Based on these data, it was hypothesized that D2 receptors released Ach that acted through muscarinic receptors to reduce GABA release. A number of experiments will test aspects of this hypothesis, including, depletion of vesicular Ach and lesions of the Ach terminals in the PFC, in order to eliminate Ach release and thus D2 mediated effects on IPSCs. These studies will provide a more comprehensive understanding of DA regulation in inhibition in the PFC, and how it might regulate cellular processes involved in working memory. [unreadable] [unreadable]